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IMMUNE SYSTEM Subjects: Immunology Study programme: General Medicine Academic year: 2015/2016 RNDr. Mira Horváthová, PhD. Department of Clinical Immunology and Allergology Faculty of Medicine SMU in Bratislava Immune system (IS) a complex network of specialized cells, cell products, tissues and molecules and their interactions incurred during the phylogenetic development of organisms Arose in nearly all organisms as response to the external environment in an effort to survive Evolution of the immune system is always co-evolution with pathogens Diffuse organ that protects the body from pathogens and others foreign substances, destroyed infected and malignant cells, and removes cellular debris What are the parts of the IS? IS - complex system organs, tissues, cells, molecules, regulatory substances - are interconnected – weight in an adult is about 1 kg of Organs of the IS primary lymphoid organs: bone marrow and thymus secondary lymphoids organs: spleen, lymph nodes, tonsils, appendix, Peyer´s patches in the gut - GALT, gut-associated lymphoid tissue MALT, mucosal-associated lymphoid tissue BALT, bronchial-associated lymphoid tissue Cell of the IS – approximately 1012 cells Subjecting whole blood to density-gradient centrifugation fractionates the sample into three constituents: erythrocytes, plasma and buffy coat. The buffy coat, a thin layer sandwiched between the other components, is less than 1% of the original whole blood sample, yet it contains the majority of the white blood cells and platelets. Leukocytes White blood cells multilobal nucleus - contain large amounts of cytoplasmic granules – granulocytes uniform nucleus – cytoplasm without granules or only a few granules - agranulocytes (35- 38%); lymphoid and myeloid lineage Agranulocytes – lymphoid lineage Lymfocytes B cells – differentiate to plasma cells that synthesize immunoglobulins • T cells – arise from bone marrow and mature in thymus • NK cells – kill abnormal cells (infected, tumour) Mononuclear cells – myeloid lineage Monocytes - 1-2 days in the circulation, tissues - several months Macrophages - part of mononuclear phagocyte system, professional phagocytes, act as antigen presentig cells (APC) Dendritic cells – Ag presentation; multiple cytoplasmic projections; lower ability of phagocytosis, myeloid and lymphoid origin Granular Leukocytes multilobal nucleus and cytoplasmic granules coloring dyes, basic or acidified Neutrophils Basophils and Mast cells Eosinophils Neutrophils Polymorphonuclear Leukocytes 45-70% of the total Leu 2-5 nuclear segments life time in the blood 6–8 hr., tissues 1-2 days new cells are formed daily 5-1010 (10 billion) professional phagocytes accute infections Basophils and Mast cells role in allergic reaction granules contain histamine, heparin and other mediators of anaphylaxis • participate in the early reactions of hypersensitivity Basophils: 0-1% in circulation Mast cells – arise from hematopoietic stem cells and occur in tissues Eosinophils 0- 5% of peripheral blood Leu bilobed granulocytes professional phagocytes eosinophilic granules – major basic protein, eosinophil cationic protein, neurotoxin, eosinophil peroxidase important role in allergic reactions and in protection against parasitic diseases MOLECULES OF IS Antibodies (Immunoglobulins) Cytokines (Lymphokines, Interleukins) Endogeneous Immunomodulators (Immunohormones) Complement System HLA molecules (antigens) Receptors THE MAIN FUNCTION OF IMMUNE SYSTEM Recognize pathogen Respond to it and remove it Remember it INNATE and ADAPTIVE immune response IS reacts to foreign dangerous agents imunological surveillance defence again pathogens viruses, bacteria, fungi, protozoa, parasites detect and remove abnormal cells e.g. tumour, damaged anti-allergen action distinguish „self“ from „foreign“ homeostasis preservation maintaining the integrity of macroorganism Antigen any substance that induces specific immune response IMMUNOGENICITY SPECIFICITY or ANTIGENICITY Scheme of complete antigen – immunogen Complete (functional) antigen consists of the macromolecular carrier and determinant groups. It has the ability to specifically react with the products of the immune response, induces the formation of antibodies. Isolated antigenic determinant hapten, has the ability to specifically react with the products of immune response, but can not induce their formation. Is called incomplete antigens Type of antigens T-cell dependent Ag T-cell independent Ag Superantigen Allergen Tolerogen Antibodies Imunoglobulins (Ig) produced by plasma cells – B cell line; part of immunoglobulin superfamily COGNITIVE FUNCTION EFFECTOR FUNCTION Affinity of antibody the strenght of the reaction between a single antigenic determinant (epitope) and a single combining site of the antibody Avidity of antibody is a measure of the overall strenght of binding of an antigen with many antigenic determinants and multivalent antibodies Antibody response to an antigen Antibody Protection of the Host Immunological memory Adaptive (or acquired immunity) creates immunological memory after initial response to a specific pathogen, leading to enhanced response after second exposure to the same pathogen. No immunological memory in innate immune system Cell surface receptors membrane receptors, transmembrane receptors communication between cells and outside world extracellular signaling molecules signal transduction Preformed receptors components of innate immunity PRR - Pattern recognition receptors TLR - Toll-like receptors KAR – Killer activation receptor KIR – Killer-inhibition receptors CR – Complement receptor FcR – bind the antibodies at their Fc region CR – complement receptors KIR, KAR – on NK cells Generated receptors BCR – B cell receptor TCR – T cell receptor TCR – T cell receptor BCR – B cell receptor Lipid bilayers CD molecule Cluster of Differentiation The identification of immune cell subsets CD45+ Leukocytes CD3+ CD3+CD4+ (Th) CD3+CD8+ (Tc) T-lymphocytes CD19+ B-lymphocytes CD14 monocytes/macrophages CD3+HLADR+ activated T-Ly CD3-CD(56+16)+ NK cells Surface adhesion molecules Immunoglobulin superfamilly ICAM-1/CD54 ICAM-2/CD102 ICAM-3/CD50 VCAM-1/CD106 Selectins E-selectin/CD62E P-selectin/CD62P L-selectin/CD62L Integrins LFA-1...CD11a/CD18 VLA-4...CD49d/CD29 Antigen presentation – a multistage process uptake of antigen by antigen presenting cell (APC) proteolytic cleavage Ag degradation - immunogenic fragments (IFs) complex IFs + HLA-molecules exposition of IFs to extracellular space recognition of IFs + HLA-molecules by T cells phenomenon of MHC restriction interaction between CD4 Th-Ly (or CD8 Tc-Ly) and HLA II. class (or I. class) on APC Endogenous pathway of Ag presentation – intracellular pathogens – viruses, tumor cells Exogenous pathway of Ag presentation – extracellular pathogens CO CO--STIMULATORY SIGNALS Immunological tolerance (IT) a state of unresponsiveness of the immune system to substances or tissue that have the capacity to elicit immune response NATURAL IT SECONDARY IT IT TO FETUS Disorders in mechanisms of immune tolerance lead to diseases AUTOIMMUNITY ALLERGY TUMOR Cytokines basic regulators of Immune system tissue hormones - proteins secreted by leukocytes and other cells act through specific receptors pleiotropic effects - exert multiple action cytokine system is redundant – each cytokine can be replaced by others produced in a cascade cytokine network Classification of cytokines Interleukins Chemokines Interferons Transforming Growth Factors Colony Stimulating Factors Tumor Necrosis Factors Other growth factors The distribution of cytokines according to function proinflammatory cytokines - TNF, IL-1, IL-6, IL-8, IL-12, ... anti-inflammatory – IL-4, IL-6, IL-10, TGF-β, ... cytokines with hematopoietic growth factor activity : IL-2, IL3, IL-4, IL-5, ... cytokines of the humoral immunity (Th2): IL-4, IL-5, IL-9, IL10, IL-13, TGF-β, ... cytokines of the cell mediated immunity (Th1): IL-1, IL-2, IL12, IL-15, IFN-γ, TNF, ... cytokines with antiviral activity: IL-28, IFN-α, IFN-β, IFN-γ Non-specific immune system mechanical barriers and mechanical reactions - skin, mucous membranes, coughing, sneezing, ... chemical barriers - eg. enzymes in saliva, NaCl (sodium chloride) in tears, HCl (sodium chloride) in the stomach chemicals - complement proteins, interferon, histamine, pyrogens cells - granulocytes: Neu, Eo, Ba; agranulocytes: Mo/Ma, NK, mast cells phagocytosis inflammation Complement key system for surveillance and immunological homeostasis abbreviation "C„ a set of about 40 executive and regulatory glycoproteins three biochemical pathway activate C system: classical, alternative and the lectin pathway components C1 to C9, factors B, D, and properdin, co-factors components are activated through cascade mechanism Complement activation Biological effects of complement CELL LYSIS C5b-C9, MAC INFLAMMATORY RESPONSE Basophils and mast cells degranulation C3a, C4a, C5a Neutrophils dagranulation C5a Eosinophils degranulation C3a, C5a Leukocytes extravasation and chemotaxis at sites of inflammation Thrombocyte aggregation C3a, C5a, C5b67 C3a, C5a Inhibition of macrophage migration and induction of macrophage spreading Bb Release of neutrophils from the bone marrow C3c Release of hydrolytic enzymes from neutrophils C5a Increase of CR1 and CR3 expression on neutrophils C5a OPSONISATION AND STIMULATION OF PHAGOCYTOSIS NEUTRALISATION OF VIRUSES SOLUBILIZATION AND REMOVAL OF IMMUNE COMPLEXES C3b, C4b, iC3b C3b, MAC C3b Receptors for complement fragments Receptor Ligand Activity Distribution CR1 (CD35) C3b, C4b, iC3b Stimulates degradation and phagocytosis Er, Ne, Ma/Mo, Eo, DC, B-ly, some T-ly CR2 (CD21) C3d, C3dg, iC3b, EBV Part of B-ly coreceptor, binds EBV B-ly, DC CR3 (CD11b/18) iC3b Stimulates phagocytosis Ne, Ma/Mo, NK, some Tly CR4 (CD11c/18) iC3b Stimulates phagocytosis Ne, Ma/Mo, NK, some Tly C3a/C4a receptor C3a, C4a Induces degranulation of Mast cells, Ba, Ne, Endothelial cells C5a receptor (CD88) C5a mast cells and basophils Induces degranulation of mast cells and basophils Mast cells, Ba, Ne, Ma/Mo, Thrombocytes, Endothelial cells Inflammatory process phylogenetically and ontogenetically the oldest defense mechanism protective response - immune cells, blood vessels, and molecular mediators eliminate the initial cause of cell injury, clear out necrotic cells and damaged tissues, initiate tissue repair Characteristics of inflammatory process Four stages Vascular response Aute cellular responses Chronic cellular responses Healing Neutrophil – important in acute inflammation Inflammatory response Various immune cells Major plasma enzyme systems Regulatory molecules Neuroendocrine regulators Inflammatory mediators cytokines, chemokines and other chemotactic factors histamine, serotonin, prostaglandins, leukotrienes lysosomal enzymes mainly from professional phagocytes acute phase proteins - serum amyloid A, CRP, complement proteins, fibrinogen, alpha-1-antitrypsin, haptoglobin, ceruloplasmin, etc. Phagocytosis Basic mechanisms of innate immunity Professional phagocytes - Ne, Eo, Mo/Ma Phagocytosis – bridge between the innate and adaptive immunity protection against pathogens – innate immune system Ag processing – adaptive immune response Phagocytosis - multistage process Specific immune system T-lymphocytes B-lymphocytes T-lymphocytes Helper Th-lymphocytes (Th1, Th2, Th3, Th17, Th9) Cytotoxic Tc-lymphocytes (perforins, toxic lymphokines- TNF-β, ...) Regulatory Treg-lymphocytes (CD4+CD25+Foxp3+) Subpopulation of T-lymphocytes Th3 CD3+CD8+ CD3+CD4+ TGF-β IL-4 IL-10 Th17 IL-17 B-lymphocytes humoral immunity arise from hematopoietic stem cells in the bone marrow differentiate into plasma cells - produce antibodies Differentiation of B-lymphocytes activation proliferation differentiation formation of memory and effector cells Disorders of immune system failures of host defense mechanisms - reduced resistance to infection – immunodeficiency pathological reactivity to external factors – allergies inadequacy in self-tolerance - pathological reactivity to internal factors - autoimmune diseases immune surveillance deficiencies - cancers Literature Immunology, 8th Edition With STUDENT CONSULT Online Access By David Male, MA, PhD, Jonathan Brostoff, MA, DM, DSc(Med), FRCP, FRCPath, David Roth, MD, PhD and Ivan Roitt, 2013 Immunology for Medical Students, 2nd Edition, With STUDENT CONSULT Online Access By Roderick Nairn, PhD and Matthew Helbert, 2007 Immunology, Ivan Roitt at al., 2006 Roitt's Essential Immunology, P. J. Delves et al., 2011